Many polymer solutions exhibit phase separation phenomena, which occur at specific temperatures characteristic of the concentration and the system (usually referred to as binodal temperatures or as cloud points). Above or below the cloud point temperature, the polymer is soluble and the solution is clear, but below or above this temperature, the polymer becomes insoluble and phase separates and the solution becomes opaque. In most polymer-solvent systems solubility decreases with falling temperature, but in some cases involving polar polymers, the opposite occurs and the polymer suddenly phase separate at a specific, higher temperature; the cloud-point temperature is in such cases a lower critical solution temperature (LCST). Polymer solutions in which the cloud point temperature occurs at low critical solution temperatures have been described in Japanese patent Nos. 85 190444; 85 208336; and 86 66707. These aqueous solutions include gels of poly-isopropylacrylamide and of isopropyl acrylamide/N-methylolacrylamide copolymers and of pyrrolidyl or piperidyl/acrylamide copolymers. Besides these acrylamides; N-iso-, N-n-, N-cyclopropylacrylamide and the corresponding methacrylamides are described in these patents, as well as N,N-diethylacrylamide as the only disubstituted acrylamide.
Thermally-sensitive polymers having an LCST in aqueous solution are well known in the art. See, e.g., Hoffman, A. “Intelligent Polymers” in Park, K, ed., Controlled Drug Delivery: Challenges and Strategies, American Chemical Soc., Washington, D.C. (1997). These polymers show fairly large physical changes (or transitions) in response to temperature, and have as a common property a balance of hydrophilic and hydrophobic groups. A thermally induced phase separation causes the release of hydrophobically bound water, and a resulting change in the conformation and properties of the polymer. The combination of a thermally sensitive polymer with a pH sensitive component can make the thermally-sensitive polymer sensitive to pH changes because the ionization, and thus hydrophilicity, of the pH-sensitive component can be changed by changing the pH.
Water soluble polymers with thermal sensitivity are of great scientific and technological importance. Such “smart” or “responsive” polymers are starting to find applications in pharmaceutical, biotechnological, chemical, and other such industries. For nonionic polymers, in most cases the thermosensitive character originates from the existence of a lower critical solution temperature (“LCST”), beyond which the polymer becomes insoluble in water.
Driven by the high promise for biomedical applications, polymers that exhibit a response in water at about 37° C. are of particular interest. The most commonly studied homopolymer (poly(N-isopropylacrylamide). PNIPAM), with a transition in water at 32° C. is not approved for human use. Furthermore, efforts to tailor the LCST of acrylamides to a temperature different than 32° C. by means of attaching hydrophobic or hydrophilic branches to these polymers, resulted in very broad transitions, that take place over tens of degrees centigrade, and do not correspond to the hydrophilic/hydrophobic balance. See, e.g. Laschewsky et al. “Tailoring of Stimuli-Responsive Water Soluable Acrylamide and Methacrylamide Polymers” Macromolec. Chem. Phys. 2001, vol 202, pg. 276-286. On the other hand, polyethylene oxide (PEO). which is currently used in many biomedical devices, has a LCST in water at about 150° C. rendering it of limited use for biomedical applications which require a temperature response.
A need therefore exists for polymers which show sharp transition temperature behavior in solution at lower temperatures. A further need exists for methods of manufacture of these polymers as well as methods for control of the transition behavior of the polymers.